Regulating vaccines at the FDA: development and licensure of Zika vaccines

KEYWORDS:

• Accelerated approval
• animal rule
• immune response
• infectious disease
• licensure pathways
• surrogate marker
• US FDA
• vaccine development
• Zika
• vaccine approval process

Infection with the Zika virus, a mosquito-borne member of the Flaviviridae family, may cause symptoms similar to those of other arbovirus infections, including fever, muscle and joint pain, malaise, and headache. While infections are often mild or asymptomatic, Zika infection during pregnancy can cause congenital brain abnormalities, including microcephaly, in infants born to mothers infected with the virus [1]. The current Zika outbreak began in 2015 in South America and quickly reached other countries around the world, including the U.S. Its rapid transmission combined with the severity of associated birth defects have mobilized the public health community and generated substantial interest in the accelerated development of vaccines to protect against this disease. However, there are challenges to the clinical development of Zika vaccines as little is known about the biology of the Zika virus, including how exposure to other flaviviruses may affect its immune response and/or course of the disease. Nevertheless, several vaccine candidates that are based on different platforms (e.g. DNA, mRNA, or inactivated organism) are in early clinical trials and thus, defining clinical development and regulatory strategies that could make an effective vaccine available will help facilitate the development of these products.

In this regard, the clinical development program and regulatory strategy for a Zika vaccine must be tailored to the particular vaccine under investigation and may differ from that of other Zika vaccines. In addition, it will be influenced by several factors including characteristics of the vaccine, available nonclinical and clinical data for the particular vaccine and/or related vaccines, proposed indication, target population, and availability of an immune correlate of protection or a surrogate end point reasonably likely to predict clinical benefit.

In the U.S., ‘traditional approval,’ accelerated approval, and ‘animal rule’ approval are potentially available pathways for Zika vaccine candidates and can be applied provided the regulatory requirements for the particular pathway are met. Irrespective of licensure pathway, an application for licensure of a Zika vaccine must include data, including chemistry, manufacturing, and controls information, to ensure manufacture of a consistently safe and effective product. Pre-licensure safety studies will need to address the potential for common adverse reactions. It usually is not necessary to address the potential for rare adverse events prior to licensure. However, where a concern exists (e.g. potentially immune-mediated outcomes such as Guillain–Barré Syndrome (GBS) which has been associated with wild-type Zika infections), post-licensure safety studies may be needed to address this possibility. While all approaches to vaccine licensure require demonstration of quality and safety, licensure may not necessarily require demonstration of efficacy in a clinical trial using a clinical disease end point such as prevention of Zika virus disease. Under U.S. FDA’s ‘traditional approval’ pathway, demonstration of vaccine effectiveness is based on a clinical disease end point or, alternatively, a scientifically well-established marker of protection (e.g. antibody response) that is applicable to the candidate vaccine. There is currently no scientifically well-established marker of protection for Zika. Thus, if the traditional approval pathway was to be considered, demonstration of effectiveness would likely be based on an end point such as prevention of Zika virus disease and/or prevention of Zika virus infection.

Products providing meaningful benefit over existing treatment for serious or life-threatening illnesses can be approved under the accelerated approval provisions contained in the Code of Federal Regulations (CFR), i.e. 21 CFR 601.40/41 [2]. For a Zika vaccine, approval under these provisions could be based on adequate and well-controlled clinical trials establishing an effect of the product on a surrogate end point (e.g. immune marker or impact on another clinical marker) that is reasonably likely to predict clinical benefit. The surrogate end point chosen could be supported by human studies (e.g. in which immune responses in vaccinated individuals were compared with those in vaccinated individuals who contract Zika) and/or nonhuman primate studies (in which a similar assessment could be made in Zika virus-challenged animals).

The incidence of Zika disease and the infrastructure for conducting clinical trials in affected areas are primary determinants of the design of phase 3 clinical end point studies to evaluate vaccine efficacy. Trials with randomization based on individual subjects and parallel vaccination of investigational and placebo groups enable the most robust assessment of vaccine efficacy. This may include challenge studies, provided ethical concerns are addressed. Alternative trials can also be considered (e.g. cluster-randomized trials) for demonstration of efficacy or effectiveness. For vaccines to protect against Zika virus diseases, foreign efficacy trials may be necessary if the disease has a low incidence in the US FDA regulations permit the acceptance of foreign clinical studies in support of an approval, provided certain conditions are met as described in the CFR, i.e. 21 CFR Part 312 [3].

Important considerations in design of clinical trials include an appropriate control group, appropriate methods for randomization, masking procedures, primary and secondary end points as well as well-defined clinical case definitions for these end points, and validated diagnostic assays to support the pivotal analyses and adherence to relevant statistical principles. It may not be possible to evaluate the most clinically concerning aspects of Zika infection/disease, for example, neurological complications including GBS or congenital infection leading to neurological malformations in pre-licensure studies. Moreover, these may occur in the absence of symptomatic infection. Therefore, prevention of Zika virus infection could be used as the primary end point for evaluation of vaccine efficacy/effectiveness in pre-licensure clinical trials provided validated assays are available to reliably detect Zika infection in subjects.

If human studies were shown to be infeasible or unethical, for ‘animal rule’ approval of a Zika vaccine, evidence for effectiveness could be derived from challenge/protection studies in an appropriate animal model(s) and clinical immunogenicity data (21 CFR 601.90-91) [4]. 21 CFR 60.90-91 permits FDA to license vaccines based on adequate and well-controlled animal studies. The results of those animal studies would need to establish that the vaccine is reasonably likely to produce clinical benefit in humans. In addition, studies demonstrating the safety of the vaccine in humans would need to be conducted. Of note, this pathway does not apply when other licensure pathways (i.e. traditional approval or the accelerated approval provisions) can be used. It is presently not clear that a Zika vaccine would be eligible for approval under the ‘animal rule’.

If Zika epidemiology precludes conduct of clinical disease end point efficacy studies, the most efficient path to support a regulatory conclusion of Zika vaccine efficacy may need to rely on immunogenicity assessments of vaccines in clinical studies. U.S. accelerated approval or animal rule approaches would also require post-licensure studies to be conducted during either the current or a future outbreak. In the case of accelerated approval, these would need to be adequate and well-controlled studies designed to verify clinical benefit, while for the animal rule the post-licensure study requirement could be met with field trials that provided additional information on effectiveness and safety. Vaccine effectiveness could potentially be confirmed using epidemiological observations such as case–control studies, which have been used to provide estimates of vaccine effectiveness in post-licensure settings.

In a public health emergency, there may be desire to make investigational vaccine available to certain individuals at high risk under a clinical study. However, this can lead to a trade-off between making vaccine available and being able to demonstrate effectiveness of the investigational vaccine to support licensure. Given the large number of Zika vaccine candidates currently under development, there is also the risk of selecting an inferior vaccine candidate for this purpose. As an alternative, some clinical trial designs can reduce the number of placebo recipients (or the amount of time that placebo recipients are observed prior to being offered vaccine) required to demonstrate vaccine effectiveness and potentially allow for increased vaccine access. However, the statistical power to establish efficacy would likely be reduced, thus necessitating postponing the trial outcome and increasing the number of subjects needed to meet statistical criteria for efficacy.

Of note, even if effectiveness of pilot vaccine lots used in clinical studies were to be established, the product may not yet be ready for licensure if other requirements, such as consistency of manufacturing, have not been met. In these situations, investigational vaccine could also be made available through FDA’s ‘Expanded Access’ provisions under Investigational New Drug Application with informed consent provided certain regulatory requirements are met [5]. Emergency Use Authorization can also potentially be used to make vaccine that does not yet meet standards for licensure available in the case of certain public health emergencies, but this would reduce the ability to determine if the vaccine was effective [6].

The goal of the scientific and public health community is to make a safe and effective Zika vaccine available as soon as possible. Regulations provide a basis for making the determination that a vaccine is safe and effective and can be licensed, and for making the determination that a vaccine can be used in certain circumstances prior to licensure. Though each vaccine candidate will require an approach that is individually developed and applied, attention to the outlined regulatory pathways will thus help to expedite the development of Zika vaccines.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was not funded.